The invention relates to processes for the preparation of derivatives of 4a, 5,9,10,11,12-hexahydro-6H-benzofuro [3a,3,2-ef] [2]benzazepine, of the general formula (I) 
or of salts thereof, wherein R2, R4, X1, X2, Y1 and Y2 are either identical or different and are hydrogen, fluorine, chlorine, bromine, iodine, a hydroxyl or alkoxy group, a lower, optionally branched alkyl group which is optionally substituted by, for example, at least one halogen, a lower, optionally branched alkenyl, group, a lower, optionally branched alkynyl group, an optionally substituted aryl, aralkyl or aryloxyalkyl group, the alkyl chain of which is optionally branched and the aromatic nucleus of which is optionally substituted, formyl or unbranched or branched alkylcarbonyl, arylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkyloxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, alkylsulfonyl, aralkylsulfonyl or arylsulfonyl which are unsubstituted or substituted by one or more halogens, or Y1 and Y2 together are =0 and wherein A is a benzene nucleus which is optionally mono- or polysubstituted by at least one lower, optionally branched alkyl group, at least one lower, optionally branched alkene group, at least one lower, optionally branched alkyne group, at least one lower, optionally branched alkoxy group, by fluorine, chlorine, bromine or iodine or by several identical or different halogens, at least one alkyl group substituted by one halogen or by several identical or different halogens, such as chloromethyl and trifluoromethyl, at least one optionally substituted aralkyl group and/or at least one hydroxyl group, primary, secondary or tertiary amino group, nitro group, nitrile group, alkylamino group, arylamino group, aldehyde group, carboxylic acid group or all derivatives of the carboxylic acid group, such as eaters, asides and halides.
The invention furthermore relates to processes for the preparation of derivatives of 4a,3,9,10,11,12-hexahydro-6H-benzofuro[3a,3,2-ef] [2]benzazepine, of the general formula (II) 
wherein R2, R4, X1, X2, Y1, and Y2 and A have the meanings given above for formula (I), Zxe2x88x92 is an organic anion of a pharmaceutically useful acid, such as tartrate, lactate, citrate, acetate or maleate, or an inorganic anion, such as fluoride, chloride, bromide, iodide, sulfate, phosphate or chlorate, R5 is hydrogen, formyl, unbranched or branched alkyl, alkenyl, aryl, aralkyl, alkylcarbonyl, arylcarbonyl or aralkylcarbonyl which are unsubstituted or substituted by at least one halogen, or branched or branched alkyloxycarbonyl aryloxycarbonyl, aralkyloxycarbonyl, alkylsulfonyl, arylsulfonyl or aralkylsulfonyl which are unsubstituted or substituted by one or more halogens.
Preferred meanings of the substituents R1-R6, X1,2 Y1,2 are R1, R2, R3, R6: hydrogen, unbranched or branched alkyl, alkenyl, aryl, aralkyl, alkylcarbonyl, arylcarbonyl or aralkylcarbonyl which are unsubstituted or substituted by one or more halogens, or any combination of these radicals, X1, X2: H, F, Cl, Br, Ixe2x88x92, t-butyl and any combination, Y1, Y2: H, O-R6, and Y1 and Y2=0, R4, R5: the preferred meanings mentioned for R1, R2, R3, R6 and unbranched or branched alkyloxycarbonyl, aryloxycarbonyl aralkyloxycarbonyl, alkylsulfonyl, arylsulfonyl or aralkylsulfonyl which are unsubstituted or substituted by one or more halogens.
Galanthamine is an alkaloid of high pharmacological activity which occurs chiefly in plants of the Amaryllidaceae type. Its action as a selective acetylcholinesterase inhibitor and its associated use for Alzheimer""s diseases are to be emphasized in particular. Galanthamine has been isolated to date from the caucasian snowdrop Galanthus woronoyi in amounts of a few kg annually at a cost of more than US$ 30,000/kg. Galanthamine syntheses have been known in principle since the end of the nineteen-sixties, but long, uneconomical reaction paths with poor overall yields have been used.
The synthesis of some compounds of the general formulae (I) and (II) given above is known per se and described in the literature. Thus N-(3-hydroxy-4-methoxyphenyl)-N-methyl -4-hydroxy -phenylethylamine has been subjected to oxidative cyclization with the aid of various oxidizing agents to give narwedine derivatives (narwedine is the precursor to galanthamine, but already has the ring structure characteristic of galanthamine) [Lit. 1-2], the yields as a rule being less than 1% of theory. Although the structure could thus be demonstrated galanthamine could not be prepared in kg amounts of pharmaceutical interest.
Optimized processes (above all Kametani, Lit. 3-7,22) describe this cyclization an N-methyl-benzamide and phenylacetamide derivatives in yields of up to 40%, but the poor overall yields render industrial utilization impossible. The literature furthermore reports the cyclization of N,N-disubstituted phenylethylamine derivatives (Lit. 8) and electrochemical (Lit. 9-12), microbiological, enzymatic (Lit. 8) and biomimetic methods (Lit. 14-15). Lit. 23 describes the preparation of narwedine from isovanillin in an overall yield of 44%, but the use of equimolar amounts of palladium and also thallium trifluoroacetate render this synthesis uneconomical. (+/xe2x88x92) Narwedine obtained by this route (Lit. 23) is enriched in the desired (xe2x88x92) narwedine in Lit. 24 and converted into galanthamine with L-Selektride in a good yield.
Lit. 8 proposes a synthesis in which the oxidative cyclization is described with a yield of 21%, but separation of the enantiomers is absent. The reduction of bromonarwedine with LiAlH4 in THF to form a 53:31 diastereomer mixture of (+/xe2x88x92) galanthamine and (+/xe2x88x92) epigalanthamine is also known.
The invention is based an the object of developing a synthesis process with which larger amounts of the title substances can be prepared in a reproducible manner and in improved yields both of the individual steps and of the overall yield.
This object is achieved according to the invention by the processes according to claim 1 and 2, the sub-claims relating to preferred and advantageous variants and embodiments of the invention. In particular, the following measures of the invention have proved to be advantageous:
Replacement of halogenated solvents, for example chloroform, by toluene. Halogenated solvents are nowadays scarcely still employed as industrial solvents because of their toxicity, the difficulties of their disposal and their ecological unacceptability. Toluene, in contrast, does not have these disadvantages.
Working up by extraction requires organic solvents. With the invention, the working up operations of most stages can be optimized such that the reaction product can usually be obtained in crystalline form from the solution. Chromatographic purification stages or extractions can thus mostly be avoided.
Furthermore, the yields can be reproduced within a very narrow range in the invention by improving the parameters and the purity of the main products and the content of by-products can be defined according to these reactions. Improved and reproducible yields of the individual stages and of, the overall yield are possible with the process of the invention. The invention provides, inter alia, a process in which bromoformylnarwedine is reduced with reducing agents. L-Selektride can be used as the reducing agent, the reduction leading diastereoselectively to N-demethylbromogalanthamine in a high yield (for example 85%), which can be converted into (xc2x1) galanthamine by N-methylation according to Eschweiler-Clark and debromination. In this process, it has not been possible to detect (+/xe2x88x92) epigalanthamine in the reaction product by chromatographic methods. Galanthamine and galanthamine derivatives can be prepared on an industrial scale by the process according to the invention via intermediates which are not described in the literature (see the compounds mentioned in claims 64 to 67).
The processes of the present invention, which are considerably improved with respect to yield and purity of the resulting products compared with the prior art and can be carried out on an industrial scale, can be described by way of example as follows:
For synthesis of derivatives of 4a,5,9,10,11,12-hexahydro-6H-benzofuro[3a,3,2-ef] [2]benzazepine, of the general formula (I) 
or of salts thereof, wherein R2, R4, X1, X2, Y1 and Y2 are either identical or different and are hydrogen, fluorine, chlorine, bromine, iodine, a hydroxyl or alkoxy group, a lower, optionally branched and optionally substituted alkyl group, a lower, optionally branched alkene group, a lower, optionally branched alkyne group, an optionally substituted aryl, aralkyl or aryloxyalkyl group, the alkyl chain of which is optionally branched and the aromatic nucleus of which is optionally substituted, a formyl group, at unbranched or branched alkylcarbonyl, arylcarbonyl, aralkyl carbonyl, alkyloxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, alkylsulfonyl, aralkylsulfonyl or arylsulfonyl which are unsubstituted or substituted by one or more halogens and Y1, Y2 can be =0 (ketone),
wherein A is a benzene nucleus, which is optionally mono- or polysubstituted by at least one lower, optionally branched alkyl, group, at least one lower, optionally branched alkene group, at least one lower, optionally branched alkyne group, at least One lower, optionally branched alkoxy group, by fluorine, chlorine, bromine or iodine or by several identical or different halogens, at least monosubstituted alkyl group [sic], such as chloromethyl and trifluoromethyl, at least one optionally substituted aralkyl group, at least one hydroxyl group, primary, secondary or tertiary amino group, nitro group, nitrile group, alkylamino group or arylamino group, aldehyde group, carboxylic acid group and all derivatives of the carboxylic acid group, such as esters, amides and halides, a process is used comprising a condensation step with subsequent reduction, an N-formylation or introduction of an N-protective group, a bromination (which can also already be carried out at the stage of isovanillin in accordance with the overall equation), in oxidative cyclization, a reduction, depending on the mature of the reducing agent also additionally an N-methylation and debromination, and a separation of the optical isomers. If required, individual process steps of those mentioned can also be omitted.
The present invention also relates to the preparation of salts of the title compounds.
The compounds of the general formula (I) can be converted into salts with organic and inorganic acids, for example:
of mineral acids, such as hydrochloric and hydrobromic acid, sulfuric acid and phosphoric acid, and perchloric acid, or pharmaceutically acceptable Organic acids, such as lactic acid, substituted and unsubstituted tartaric acid, acetic acid, salicylic acid, citric acid, benzoic acid, xcex2-naphthoic acid, adipic acid and the like.
The processes of the invention in some cases lead to new compounds. The new compounds include:
bromogalanthamine of the formula 
epibromogalanthamine of the formula 
N-demethylbromogalanthamine of the formula 
and
N-demethyl-epibromogalanthamine of the formula 
The invention also relates to the preparation of salts of the substituted derivatives of 4a,5,9,10,11,12-hexahydro-6H-benzofuro[3a,3,2-ef]benzazepine, of the general formula (II) 
in which R2, R4, X1, X2, Y1 and Y2 and A have the meanings given above for formula (I) and Zxe2x88x92 is an organic anion of a pharmaceutically useful acid, such as tartrate, lactate, citrate, acetate, maleate and the like, or an inorganic anion, such an a fluorine, chlorine, bromine or iodine anion, or a sulfate or phosphonate or chlorate anion, R5 is a hydrogen atom, a lower, unbranched or branched alkyl radical, aryl or an aralkyl radical which is branched or unbranched in the alkyl chain, by the process described above by way of example.
The compounds obtainable according to the invention and salts thereof contain at least two asymmetric cantors and therefore occur in several stereoisomeric forms. The invention also relates to the separation of the resulting diastereomers or racemates into the optically puts antipodes and mixtures thereof.
The abovementioned steps can be carried out generally and by way of example an follows:
1. Condensation and reduction 
To prepare the compounds of the general formulae (I) and (II), substituted derivatives of the general formula (V) where R4=H are prepared by a procedure in which a compound of the general formula (III) wherein R1 and R2 are hydrogen, a lower, unbranched or branched alkyl or an aryl or aralkyl which in branched or unbranched in the alkyl chain, as well as alkyl-carbonyl, aryl-carbonyl and aralkylcarbonyl, or together (R1=R2=xe2x80x94CH2xe2x80x94) an alkyl group or a combination of these radicals, X1=H, fluorine, chlorine, bromine, iodine or t-butyl is subjected to a condensation reaction with tyramine or substituted tyramine (R3=hydrogen, a lower unbranched or branched alkyl, aryl or an aralkyl which is branched or unbranched in the alkyl chain, as well as alkylcarbonyl, arylcarbonyl, and aralkylcarbonyl). The procedure here can be as follows:
An equimolar solution of (III) and (IV) in toluene, xylene or benzene or mixtures of these solvents with higher alcohols, chiefly toluene with n-butanol, in ratios of 9:1 to 1:9, chiefly 1:1, in concentrations of 1-30%, is reacted at the reflux temperature and water is separated off. The solvent is then separated off by distillation and recovered to the extent of  greater than 95%, and the is dissolved in alcohol, such as methanol, ethanol, n-propanol, i-propanol, methylglycol or ethylglycol, water, glacial acetic acid or mixtures of these solvents, chiefly methanol, in concentrations of 1-30% and reduced by addition in portions of 0.6 to 5 equivalents, preferably 0.65 to 0.7 equivalent, of reducing agents, such as sodium borohydride, potassium borohydride, sodium cyanoborohydride and LiAlH4, and mixtures of these, but chiefly sodium borohydride, in powder or granule form, at a temperature from xe2x88x9230xc2x0 C. up to the reflux temperature. The condensation product (V) is filtered off from the alcoholic solution as the first fraction by filtration in yields of 80 to 85%. Working up of the alcoholic solution by distillation to 15 to 30% of the volume and filtration of the 2nd fraction increases the yield to 90 to 95% of theory. Alternatively, the reaction solution can be poured onto water, whereupon crystalline product (V) precipitates out and, after filtration with suction and drying, is obtained in yields of up to 95%.
2. N-Formylation or N-protective group:
Starting compounds for the oxidative cyclization of the formula (V) where R4=formyl or unbranched or branched aralkyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkyloxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, alkylsulfonyl, aralkylsulfonyl or arylsulfonyl which are unsubstituted or substituted by one or more halogens are prepared by reaction of the compounds (V) where R4xe2x95x90H with the corresponding acids, esters, anhydrides, halides, azides, carbonates or other reactive derivatives of these protective groups.
In particular, a compound of the general formula (V) where R4xe2x95x90H can be reacted in solvents such as THF, dioxane, DMF, toluene, xylene or mixtures of these solvents with the equimolar to 50 times the molar amount of the ethyl formate and catalytic amounts of formic acid (0.001 to 1 equivalent) at a temperature from 0xc2x0 C. to the reflux temperature to give a compound of the general formula (V) where R4xe2x95x90CHO. The solvents are removed in this process by vacuum distillation, the distillation residue crystallizes by addition in portions of water and ice and the product is obtained in yields of  greater than 90% at a content of  greater than 95% by filtration.
3. Bromination:
If, in compounds of the general formula (V) where R1, R2, R3=a lower unbranched or branched alkyl, aryl, aralkyl, alkylcarbonyl, arylcarbonyl or aralkylcarbonyl, X1, X2xe2x95x90H, R4=formyl, or unbranched or branched aralkyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkyloxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, alkylsulfonyl, aralkylsulfonyl or arylsulfonyl which are unsubstituted or substituted by one or more halogens, with a content of 90 to 100% in solvent mixtures of halogenated hydrocarbons, such as chloroform or methylene chloride, with alcohols (methanol, ethanol, methylglycol, ethylglycol, ethylene glycol, n-propanol, i-propanol) in ratios of 9:1 to 1:9, preferably 3:2 to 2:3, and of pure alcohols (methanol, ethanol, methylglycol, ethylglycol, ethylene glycol, n-propanol, i-propanol) and mixtures thereof with one another, preferably ethanol/methylglycol, in ratios of 9:1 to 1:9, preferably 3:2 to 2:3, with water contents of 0 to 5%, preferably 0 to 0.2%, at a temperature of xe2x88x9280 to +60xc2x0 C., preferably xe2x88x9240 to 0xc2x0 C., in a concentration of 0.5 g to 20 g/100 ml of solvent, the reaction is carried out with 1.0 to 3.0, preferably 1.4 to 1.7 equivalents of a bromine reagent which is obtained by addition of elemental bromine into the solvents mentioned in a concentration of 1 to 90%, preferably 2 to 10%, with addition times of the bromine reagent of 10 minutes to 4 hours, preferably 15 to 30 minutes, the compound of the formula (V) where X1xe2x95x90Br is obtained in yields of 90 to 96% of theory after a reaction time of 0.5 to 24 hours, preferably 30 to 60 minutes, and after working up (concentration by distillation to 10 to 25% of the volume and pouring onto 10 to 50 times the amount of ice-water, filtration and drying).
Preparation of the intermediate (V) where X1xe2x95x90Br, R4xe2x95x90CHO or polybrominated intermediate:
Route 1 (see page 24, overall equation): if a compound of the formula (V) where X1, X2xe2x95x90H and R4xe2x95x90CHO is brominated in accordance with the working instructions given, for example, 82% of product, 6% of precursor, 8% of by-product where X2xe2x95x90Br and 5% of more highly brominated products are obtained. (HPLC, Lichrosorb RP 18, 5xcexc, 300/4 mm, eluant MeOH/H2O 6:4 at 280 nm). If the bromination method is changed, the ratios of the products stated also change (a higher content of more highly brominated products is usually formed). After the oxidative cyclization, in addition to the desired compound of the general formula (I) where X1xe2x95x90Br, R4xe2x95x90CHO and Y1xe2x95x90Y2xe2x95x90O, [lacuna] could be detected in the precursor in contents corresponding to the content of the compound of the general formula (V) where X1xe2x95x90X2xe2x95x90Br, R4xe2x95x90CHO (HPLC, Lichrosorb Si 60, 10xcexc, 300/4 mm, eluant: CHCl3/MeOH 95:5 at 254 nm) and isolated by means of preparative chromatography (silica gel 60, CHCl3:MeOH 1-5%). After reduction with L-Selektride or with other reducing agents, more highly brominated narwedine (X1xe2x95x90X2xe2x95x90Br) is either likewise reduced to galanthamine or separated off by preparative chromatography.
Route 2: (see page 24, overall equation). Starting from veratrumaldehyde, via 6-bromo-isovanillin, the compound of the formula (V) where X1xe2x95x90Br, R4xe2x95x90CHO can be prepared by condensation and N-formylation without more highly brominated by-products.
4. Oxidative cyclization:
For oxidative cyclization of compounds of the general formula (V) where R2=hydrogen, a lower, branched or unbranched alkyl, aryl, or an aralkyl which is branched or unbranched in the alkyl chain, or alkyl-carbonyl, arylcarbonyl and aralkyl-carbonyl or a combination of these radicals X1xe2x95x90H, fluorine, chlorine, bromine, iodine or t-butyl, R4=formyl, or unbranched or branched aralkyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkyloxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, alkylsulfonyl, aralkylsulfonyl or arylsulfonyl which are unsubstituted or substituted by one or more halogens, R3=hydrogen, to give a compound of the general formula (I) where R2, R4, X1 are as above, Y1, Y2xe2x95x90O (ketone) and X2xe2x95x90H or Br, the reaction is carried out in solvents, such as chloroform, methylene chloride, ethyl acetate, THF, dioxane, glacial acetic acid, water, mixtures thereof with alcohols (methanol, ethanol, methylglycol, ethylglycol, ethylene glycol, n-propanol, i-propanol) in ratios of 9:1 to 1:9, and also toluene, xylene or benzene, chiefly xylene and toluene, in a concentration of 0.05 g to 10 g/100 ml of solvent, with bases, such as sodium hydrogencarbonate, potassium carbonate, NaOH, KOH or pyridine, preferably potassium carbonate, in a concentration of 0.1% to a saturated solution or suspension, chiefly 5 to 20%, and oxidizing agents, such as Pb(OAc)4, KMnO4, FeCl3, potassium ferricyanide of H2O2, preferably potassium ferricyanide, 4-10 equivalents, preferably 5.5-6 equivalents, if necessary with addition of phase transfer catalysts, such as Aliquat or crown ethers, as well as ascorbic acid, CuCl or trifluoroacetic acid, at a temperature from xe2x88x9240xc2x0 C. to the reflux temperature, chiefly 50 to 80xc2x0 C., and by rapid addition or addition in portions of the precursor as a solid, as a solution or as a suspension in a solvent, preferably as a solid, with a reaction time of 10 minutes to 72 hours, chiefly 15 to 45 minutes, with vigorous mechanical stirring, preferably using a stirrer and a homogenizer, if necessary under an inert gas, such as N2, CO2 or argon, chiefly argon. Working up by filtration, phase separation and vacuum distillation of the toluene phase gives the crude product in yields of 5 to 65%, from which yields of 5 to 50% are obtained by purification of the cyclization products.
5. Reduction:
For reduction of compounds of the general formula (I) in which R2 is a lower unbranched or branched alkyl, aryl, aralkyl, alkylcarbonyl, arylcarbonyl or aralkylcarbonyl, X1, X2 are fluorine, chlorine, bromine, iodine or t-butyl, R4 is formyl, or unbranched or branched aralkyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkyloxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, alkylsulfonyl, aralkylsulfonyl or arylsulfonyl which are unsubstituted or substituted by one or more halogens and Y1, Y2xe2x95x90O (bromonarwedine type), with hydride reagents, such as DiBAlxe2x80x94H, DiBAlxe2x80x94H/ZnCl2, Al isopropylate, Red-Al, K-Selektride, L-Selektride, KS-Selektride, LS-Selektride, Li-tri-t-butoxy-AlH, Li-tri-ethoxy-AlH, 9-BBN, Superhydride, NaBH4, Zn(BH4)2, AlH3, AlCl2H or a combination of these reducing agents, a procedure can be followed in which the reduction is carried out by addition of the reducing agent in equimolar amounts or in excess to the starting substance or inverse addition of the starting substance to the reducing agent in an inert solvent, such as diethyl ether, THF, dioxane, toluene, xylene or benzene, at temperatures from xe2x88x9250xc2x0 C. to the reflux temperature. After alkaline (chiefly NH4OH) or acid (chiefly 2N HCl) working up and subsequent extraction with solvents such as toluene, xylene, benzene, ethyl acetate, ether, chloroform or methylene chloride, the crude product is purified by chromatographic processes and, as required, the diastereomers are isolated or the crude products are reacted further directly.
In particular, N-demethylbromogalanthamine is obtained diastereoselectively in yields of 70-85% of theory, after purification by column chromatography, by reduction of bromo-N-formylnarwedine (in contrast to Lit. 24, where narwedine is used) with L-Selektride or K-Selektride. No epi-N-demethylbromogalanthamine could be detected by chromatographic methods.
N-demethylbromogalanthamine is converted into bromogalanthamine in yields of 80-90% of theory by N-methylation, for example by boiling up for 10 minutes to several hours in a 5- to 50-fold excess of formic acid and aqueous formaldehyde solution.
Bromogalanthamine is converted into galanthamine, for example, by heating at the reflux temperature with a 5- to 50-fold molar excess of formic acid and triethylamine in the presence of 0.1 to 15% of palladium/active charcoal catalyst for 1 to 12 hours, bromine being eliminated. Yield: 70 to 80% of theory.
The reaction stages can also be carried out without isolation and purification of the intermediates.
A mixture of N-demethylbromogalanthamine and epi-N-demethylbromogalanthamine in a ratio of about 1:1 is obtained by reduction of the precursor with Li-tri-t-butoxy-AlH.
Reduction with DiBAlxe2x80x94H gives 43% of bromogalanthamine and 41% of epibromogalanthamine.
Reduction with Lixe2x80x94AlH4/anhydrous H2SO4 also gives bromogalanthamine and epibromogalanthamine in a ratio of about 3:1.
The reduction can be carried out, for example, as described below:
For reduction of a compound of the general formula (I) with R2=alkyl, X1xe2x95x90Br, R4xe2x95x90CHO, X2xe2x95x90H, Y1, Y2xe2x95x90O (ketone), the precursor is dissolved in a solvent such as THF, dioxane or other ethers, chiefly THF, in concentrations of 0.1 to 20 g/100 ml by heating. 3 to 5, chiefly 3.5 equivalents of L-Selektride, chiefly as a 1 molar solution in THF, are then added at a temperature of from xe2x88x9250xc2x0 C. to the reflux temperature, chiefly at 0-20xc2x0 C., and the mixture is reacted by stirring for 20 minutes to 48 hours, chiefly one hour. The complex formed with the reducing agent is destroyed by addition of water and ammonium hydroxide and excess organic solvent is evaporated off in vacuum by heating to not more than 30xc2x0 C. Extraction with solvents such as ethers (e.g. diethyl ether), ethyl acetate, butyl acetate, chloroform, methylene chloride, toluene, benzene or xylene gives N-demethylbromogalanthamine in crude yields of 90 to 100% of theory.
For monomethylation of N-demethylbromogalanthamine, a solution of N-demethylbromogalanthamine in a 5- to 30-fold molar excess of formic acid and aqueous formaldehyde solution (37%) is heated at the reflux temperature, with or without an organic solvent, for 10 minutes to 2 hours, chiefly 15 to 20 minutes.
For debromination of bromogalanthamine or epibromogalanthamine, bromo- or epibromogalanthamine is heated at the reflux temperature in a 5- to 50-fold molar excess of formic acid and triethylamine, with or without an organic solvent, in the presence of 0.1 to 15% of palladium/active charcoal catalyst for 1 to 12 hours, chiefly 2.5 hours.
For reduction of a compound of the general formula (I) where R2=alkyl, X1xe2x95x90Br, R4xe2x95x90CHO, X2xe2x95x90H, Y1, Y2xe2x95x90O (ketone), the precursor is suspended in an inert organic solvent, such as benzene, toluene or xylene, chiefly toluene, in a concentration of 0.1 to 20 g/100 ml, and 3 to 5, chiefly 3.5 equivalents, of DiBAlxe2x80x94H, as a chiefly 1.5 molar solution in toluene, are added dropwise at a temperature from xe2x88x9250xc2x0 C. to reflux temperature, chiefly 0 to 20xc2x0 C. The mixture is then stirred at this temperature for 20 minutes to 12 hours, chiefly 30 minutes to 1.5 hours, the complex formed is destroyed with water and ammonium hydroxide, the mixture is extracted with toluene and the crude product (90 to 100% of theory) is separated into 43% of bromogalanthamine and 41% of epibromogalanthamine by means of column chromatography (silica gel, acetone/hexane 1:1).
6. Separation of optical isomers:
To separate chiral 4a,5,9,10,11,12-hexahydro-6H-benzofuro[3a,3,2-ef] [2] benzazepines of the general formula (I), (Y1xe2x95x90H, OH; Y2xe2x95x90, OH) in which A, R2, R4, X1 and X2 have the abovementioned meanings, into the enantiomerically pure antipodes, the method of fractional crystallization of salts with chiral acids can be used. The separation of the (+) and (xe2x88x92) isomers of the compounds of the narwedine type (compounds of the general formula (I) in which Y1 and Y2 together are xe2x95x90O (ketone)) by fractional crystallization is carried out by a procedure in which a solution or suspension of the optical isomer mixture in 5 to 50 times the amount of a solvent, such as water, methanol, ethanol, propanol, isopropanol, acetone or mixtures of these solvents, chiefly methanol, is combined with the equimolar amount or an excess of a chiral acid (unsubstituted or mono- or polysubstituted + or xe2x88x92 tartaric acid, citric acid, lactic acid, xcex1-methoxyphenylacetic acid, camphorsulfonic acid and derivatives thereof, preferably di-p-tolyl (+) tartaric acid), which is dissolved in one of the abovementioned solvents, the solution is seeded with crystals prepared from naturally occurring (xe2x88x92) galanthamine derivatives and chiral organic acids, such as di-p-tolyl (+) tartaric acid, and left to stand at xe2x88x9240 to +20xc2x0 C., preferably 0xc2x0 C., for 2 to 24 hours or longer, and the crystals formed are filtered off and dried, excess NH4OH is then added, the mixture is extracted with organic solvents, such as chloroform, methylene chloride, ethyl acetate, butyl acetate, diethyl ether, t-butyl methyl ether, dibutyl ether, petroleum ether, xylene, benzene, toluene or similar solvents, and the corresponding (xe2x88x92) galanthamine derivative is isolated by distillation of the solvent.
In this process, concentration of the mother liquor, taking up in excess NH4OH, extraction with an organic solvent (as mentioned above) and evaporation gives further fractions of galanthamine, from which the (+) galanthamine derivatives can be obtained in a manner analogous to that above with the aid of the chiral organic acids, such as, for example, di-p-tolyl (xe2x88x92) tartaric acid.
The products obtained according to the invention can be purified by a process customary in chemistry, for example fractional distillation, crystallization or chromatography.
W. C. Shieh and J. A. Carlson report in J. Org. Chem. 1994, 59, 5463-5465 the (xe2x88x92)galanthamine is a selective acetylcholinesterase inhibitor which strengthens the cholinergic function and is considered as a product for treating individuals suffering from Alzheimer""s disease.
In order to prepare enantiomerically pure (xe2x88x92)galanthamine it is proposed to add catalytic amounts of (xe2x88x92)narwedine seed crystals or (+)-galanthamine seed crystals to (xc2x1)narwedine in solution and to allow crystallization to take place. In this procedure, (xe2x88x92)narwedine crystallizes out in the form of white crystals from the solution containing (xc2x1)narwedine. To convert (xe2x88x92)narwedine to (xe2x88x92)galanthamine by reduction, a diastereoselective reduction of enantiomerically pure narwedine is proposed. (xe2x88x92)Narwedine obtained by the diastereoselective crystallization is reduced stereospecifically by means of L-Selektride to (xe2x88x92)galanthamine in a yield of almost 99% at xe2x88x9278xc2x0 C. For the two-stage process (crystallization and reduction), overall yields in the conversion of racemic narwedine to (xe2x88x92)galanthamine of 90% are quoted. With regard to the preparation of (xc2x1)narwedine reference is made to Lit. 23 (Holton et al.), a method in which stoichiometric amounts of palladium and thallium are required.
One of the disadvantages of the process described is that the reduction has to be carried out under the described process conditions at xe2x88x9278xc2x0 C. Furthermore, only a semi-microbatch (285 mg of precursor) is described, which is carried out in about 200 times the amount of solvent and is worked up chromatographically using CH2Cl2/methanol (6:1).
Reaction equations of the processes according to the invention are shown below.




According to one variant of the process of the invention, narwedine can be obtained starting from the cyclized compound of the general formula (I) where Y1, Y2=O (ketone) via the introduction of a cyclic ketal as a protective group (Y1, Y2=substituted or unsubstituted cyclic ketal or thioketal, for example propylene glycol; Oxe2x80x94CH2xe2x80x94CH2(CH3)xe2x80x94O), subsequent reduction with LiAlH4 and splitting off of the ketal protective group. Racemic narwedine (or a compound of the general formula (I) in which Y1, Y2 are xe2x95x90O (ketone)) can be enriched by addition of catalytic amounts of (+)galanthamine or of (xe2x88x92)narwedine and (xe2x88x92)narwedine can be obtained with an enantiomeric purity of  greater than 98%.
The advantage of this variant of the invention is that the unwanted enantiomer can be converted into the desired enantiomer.
Racemic narwedine can be enriched to (+)narwedine in a similar manner by addition of catalytic amounts of (xe2x88x92)galanthamine or (+)narwedine. Enriched narwedine is converted into enantiomerically pure galanthamine in a good yield with L-Selektride, it being possible for either the free base or, directly, the hydrobromide to be obtained by appropriate working up. Galanthamine hydrobromide can be obtained with an enantiomeric content of  greater than 99% by crystallization of the hydrobromide. The content is determined by measurement of the optical rotation and by quantitative determination of the enantiomers by means of microcapillary electrophoresis in chiral electrolyte.
The abovementioned steps can be carried out generally and by way of example as follows:
7. Introduction of the protective group:
For introduction of a ketal protective group the compound of the general formula (I) where Y1, Y2 are xe2x95x90O (ketone), X1 is Br and R1 is CHO is heated at the reflux temperature in solvents, such as benzene, toluene or xylene, but chiefly toluene, together with 1 to 30 times the amount of diols, such as ethylene glycol or propylene glycol, or dithiols, such as 1,3-dithiopropane, in the presence of catalytic amounts of p-toluenesulfonic acid or concentrated sulfuric acid or other acids for several hours using a water separator. The mixture is subsequently cooled and the diol phase (dithiol phase) is separated off and extracted with toluene and the ketal (thioketal) obtained is isolated by evaporation of the toluene phases.
8. Reduction, splitting off of the protective group:
Purified or crude ketal (thioketal) of the general formula (I) (chiefly where X1 is Br and R4 is CHO) is converted into narwedine by reduction with LiAlH4 and subsequent splitting off of the ketal group. For example, the propylene glycol ketal of the compound of the general formula (I) is dissolved in THF, 3 to 5 times the stoichiometric amount of LiAlH4 are added and the mixture is heated at the reflux temperature for 12 hours. Any X1Br is thereby also converted into X1H and R4CHO is converted into R4CH3. Decomposition of the excess LiAlH4 with NH4OH, filtration and extraction with EtOAc gives the ketal-protected compound of the general formula (I) of the narwedine type. Heating the crude product in an acid, chiefly 2N hydrochloric acid, and rendering the mixture alkaline with NH4OH gives the compound of the general formula (I) of the narwedine type in a good yield (about 80%). If the mixture is stirred with LiAlH4 at xe2x88x9210xc2x0 to 0xc2x0 C. for 2 hours and then hydrolyzed with NH4OH and extracted with EtOAc, ketal-protected N-demethylbromonarwedine can be obtained. In a manner comparable to that of reduction with L-Selektride, a compound of the general formula (I) where R4 is CH2xe2x80x94OH is intermediately formed, and is decomposed during the hydrolysis to give the N-demethyl compound. By treatment in 2N HCl the ketal group can be split off and a compound of the demethyl-bromo-narwedine type can be obtained. Alkylation of the O-protected or unprotected compounds of the demethyl-bromo-narwedine type or introduction of an N-protective group and splitting off of any O-protective group present gives differently substituted narwedine of the general formula (I) where Y1, Y2=O (ketone), and where R4 is substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl or aralkyl or any protective group or quaternized compounds of the general formula (II). Debromination, for example with Zn/CaCl2, gives N-substituted compounds of the narwedine type.
If a compound of the general formula (I) where Y1, Y2=ethylene glycol ketal is heated at 45-50xc2x0 C. with LiAlH4 in THF for 12 hours, correspondingly ketal-protected narwedine is formed. If the pressure is heated at the reflux temperature (65-68xc2x0 C.) for 24 hours, the cyclic ketal structure opens up and a product where Y1 is xe2x80x94CH2xe2x80x94CH2xe2x80x94OH and Y2 is H is formed, but this can likewise be converted into a compound of the narwedine type by brief heating in an acid, chiefly 2N HCl.
It is interesting that the reduction with LiAlH4 leads to demethyl-bromo-narwedine ketal at 0xc2x0 C., to narwedine ketal at 45xc2x0 C., to galanthamine hydroxyethyl ether at 70xc2x0 C. over 48 hours and to narwedine at 45-70xc2x0 C. with subsequent treatment with HCl (also splits the ketal).
Reduction of a ketal-protected compound of the general formula (I) where X1 is Br and R4 is CHO with Zn/CaCl2 leads to reduction of the bromide, to splitting off to the ketal group but to retention of R4 CHO.
9. Enrichment:
A racemic compound of the general formula (I) where Y1, Y2=O (ketone), R4 is CH3 is heated at the reflux temperature in a solvent such as water, methanol, ethanol, n-propanol, butanol, methylene glycol, ethylene glycol or mixtures of these solvents with 1 to 30% of triethylamine or similar bases, and optically pure compounds, for example (+)galanthamine or (xe2x88x92)narwedine, are added. For example, either (+)galanthamine or (xe2x88x92)narwedine are used for (xe2x88x92)narwedine, and for (+)narwedine, for example, (xe2x88x92)galanthamine or (+)narwedine are used and the mixture is cooled slowly in stages.
The mixture is preferably stirred at 40xc2x0 C. for 1 to 14 days and then cooled to 0-20xc2x0 C., and the optically enriched crystals which have precipitated out are isolated and an enantiomeric content of  greater than 98% is determined by means of microcapillary electrophoresis. Optical rotations of 405-407xc2x0 C. (20xc2x0 C., c=1/CHCl3), for example, are achieved here for narwedine. Determination by means of microcapillary electrophoresis in chiral electrolytes gives an enantiomeric content of  greater than 98%.
10. Reduction:
The enantiomerically pure compound of the narwedine type (Y1, Y2=O, ketone) can be converted diastereoselectively into the enantiomerically pure compound of the galanthamine type (Y1 or Y2 is OH) with L-Selektride analogously to the instructions already given. Working up with aqueous HBr gives the corresponding galanthamine hydrobromide with an enantiomeric content of  greater than 99%, in a yield of 87-95% of theory.
11. Splitting off of bromide:
A compound of the general formula (I) where X1 is Br is dissolved in 5 to 50 times the amount of a solvent, such as water, methanol, ethanol, n-propanol, iso-propanol, n-butanol or mixtures thereof, chiefly 70% of ethanol, 1 to 5 times the amount of zinc powder and 1 to 10 times the amount of CaCl2 are added and the mixture is stirred. After on average about 1 to 2 hours, the solid is filtered off and the solution evaporated and chromatographed (silica gel 60, solvent for example acetone) to give 80 to 85% of debrominated product.
Compared with the method described in Lit. 24, it has been possible to improve the process such that a procedure on an industrial scale is possible. For example, the precursor is added in powder form to a preferably 1 molar solution of L-Selektride in THF at room temperature, the mixture is stirred for one hour, methanol is added and the mixture is evaporated. Taking up in ethanol (for example 5-30 times the amount) and acidification with aqueous KBr gives galanthamine hydrobromide in yields of 90 to 95% at an enantiomeric content of  greater than 99%.
The process variant described leads in some cases to novel compounds, or novel compounds are formed as intermediates. The novel compounds are:
Bromo-N-formyl-narwedine propylene glycol ketal (5) 
Narwedine propylene glycol ketal (6) 
Bromo-N-formyl-narwedine ethylene glycol ketal (7) 
Narwedine ethylene glycol ketal (8) 
O-(2-Hydroxyethyl)galanthamine (9) 
Bromo-N-demethyl-narwedine ethylene glycol ketal (10) 
Bromo-N-benzyl-narwedine ethylene glycol ketal (11) 
Bromo-N-demethylnarwedine (12) 
The numbers assigned to these compounds are also used in the reaction equations reproduced below.


According to a further variant of the invention, the procedure used for preparing racemic compounds of the narwedine type is such that a compound of the general formula (Ia) 
in which R2, R4, X1 and X2 have the meanings given in connection with the general formula (I), Z1 and Z2=O, S or N and Y1 and Y2 are xe2x95x90O (ketone) is prepared by oxidative cyclization of a compound of the general formula (Va) 
in which R1, R2, R3, R4, X1 and X2 have the meanings given in connection with the general formula (V) and Z1 and Z2 are xe2x95x90O, S or N.
The product is subsequently converted, for example in a manner similar to stage 7.) described above, into a ketal or thioketal or cyclic ketal or cyclic thioketal, reduced with a reducing agent such as LiAlH4 similar to stage 8.) described above, isolated as ketal or thioketal, or converted by preferably acidic hydrolysis into the corresponding compound of the narwedine type. The equation is given in the review xe2x80x9cSynthese von Narwedin xc3xcber Benzazepinion-Typxe2x80x9d (for: Z2=H2).
A by-product which can be formed in various concentrations as a result of alcoholysis is a compound of the formula (VI) 
in which R2, R4, X1, X2, Z1 and Z2 have the meanings stated in connection with the general formula (Ia) and R7 corresponds to the alcohol or thiol used for preparing the ketal, for example xe2x80x94Oxe2x80x94CH2CH(CH3)xe2x80x94OH (propylene glycol radical).

The reduction of the compound of the general formula (Ia) in which R2, R4, X1 and X2 have the definitions given in connection with the general formula (I), Z1 and Z2=O, S, or N, and Y1 and Y2 are xe2x95x90O (ketone) with L-Selektride gives a compound of the formula (Ia) where Y1=OH, Y2=H.
The reduction of a compound of the formula (Ia) where Y1, Y2=O with LiAlH4 gives a mixture of the galanthamine type (Y1=OH, Y2=H) and epigalanthamine type (Y1=H, Y2=OH) in a ratio of about 5:3, where X1, X2=Br are reduced to X1, X2=H and Zxe2x95x90O is reduced to Zxe2x95x90H2.
The described process variant leads in part to novel compounds: 
Examples of the processes of the invention are given below: